The clinical efficacy, toxicity, and immunological effects of halogenated adenosine analogs, such as fludarabine and chlorodeoxyadenosine, are being studied in patients with autoimmune disorders. These agents primarily affect lymphoid cells because these cells contain an enzyme necessary for activation of these compounds. Previous investigations employing these drugs in patients with low grade lymphoid malignancies have shown that they selectively target immune cells by inducing a physiologic form of cell death called apoptosis. Their effects on the clinical course of immunologic diseases, as well as on the function of immune cells have not been characterized. Six patients have been entered into a study for treatment of refractory membranous nephropathy. To date, no major or unexpected toxicities have been encountered. Fludarabine treatment has resulted in sustained B and T lymphopenia (B>T). We are attempting to determine whether the level of lymphopenia should be a major determinant of safe drug doses; no substantive changes in total immunoglobulin or antibody levels have been seen. At the low doses of fludarabine used to date, no measurable clinical effects have been noted on the nephropathy. In contrast, significant clinical effects have been observed in eight patients with rheumatoid arthritis who have completed this therapy.